Paradigm-shifting discoveries are few and far between. But neuroscientist Carla Shatz has made several. Shatz, a professor of biology and neurobiology at Stanford University, has spent her career exploring how the brain develops and learns. Her journey began with vision. In adults, precisely arranged columns of neurons convey visual information from the eyes to the brain. These visual circuits take shape from the jumble of cells in the early fetal brain some time before a baby is born.

Biologists had believed that only hard-wired genetic programming could sculpt such precise circuitry before birth. Shatz instead found that the fetal eye sends test patterns to the brain that tune up the visual circuits before vision is even possible.

The finding was so surprising that many biologists didn’t believe it. But it turned out that this sort of circuit testing happens throughout the brain very early in development. These findings revealed how the brain lays the foundation for a lifetime of learning.

As Shatz investigated these early test patterns, she revealed key molecules that sculpt neural circuits. This won over skeptics, and also proved something that scientists had long suspected: that activity strengthens the connections between neurons. Meanwhile, inactive connections are removed by a process called synaptic pruning. These observations shaped today’s understanding of neuroplasticity, changes in brain structure and organization that occur as we learn, adapt and think. They also led Shatz to coin the phrase, “Cells that fire together, wire together”— a maxim that guides modern neuroscience.

In 2016, Shatz and Professors Eve Marder at Brandeis University and Michael Merzenich at University of California, San Francisco, were awarded the Kavli Prize in Neuroscience for uncovering how experience and neural activity reshape brain circuits. Now, Shatz outlines the next big questions about neuroplasticity, and how solving them could help treat Alzheimer’s disease, make the adult brain more youthful, and uncover how brain cells and circuits create consciousness.

Can we restore our childhood capacity for learning?

It’s difficult to learn how to speak French without an accent as an adult, but we can learn many different languages and speak them perfectly if we learn them during childhood. Why is that? We discovered molecules that are turned on in adulthood that apply the brakes to learning. One of these molecules regulates the ability of the brain to remove synaptic connections between nerve cells, which are absolutely critical for learning and memory. If we give adult mice a pill that blocks this molecular brake on learning, we restore juvenile-like neuroplasticity. The treated mice have more synaptic connections, and they are better at navigating a complicated maze. The results suggest that being able to retain more connections in our brain makes us better able to learn new things.

Illustration by Falconieri Visuals

Can we visualize the circuitry of a working human brain?

The brain has trillions of synaptic connections, yet neuroscientists have no way of looking at all of them in a noninvasive way in humans. Techniques like magnetic resonance imaging allow us to observe brain function, but, sadly, they provide only a coarse image. It’s like looking at Earth from the Moon. You can see New York City lit up at night, but what you really want is a resolution that would allow you to see the details— each of the lights in all of the homes at once. That’s going to take every tool in our toolkit — and new methods for monitoring all those neurons, collecting all the data, and working out the spatial and temporal organization of the computations as they happen. But it’s what we will need to really understand both how the human brain computes at the level of circuits and synapses, and what goes wrong with brain wiring in neurological diseases.

Can we help Alzheimer’s patients recover lost memories?

In Alzheimer’s disease, it’s clear that the memory loss is due to the pruning or loss of synaptic connections. It gets to be pretty grim if you’re losing the connections where your memories are stored — in a way, you’re losing your personality and yourself. There is a family of molecules that are important for synaptic pruning. Maybe if we block their functions, we could prevent the loss of these connections in Alzheimer’s disease and treat the disease and treat memory loss. That would be incredibly exciting.

How does brain biology generate the mind?

This is a huge challenge and a very exciting area of research. How do you bridge the gap between molecules, cells and circuits, and how we think and feel, and even the unanswered question of consciousness? We’ve been so reductionist in our approach to understanding the biology of the brain. What’s exciting now is that other areas of science and technology are being brought to bear to bridge this gap, including engineering, computer science, artificial intelligence, and even deep learning techniques. We pioneered this kind of collaboration at Stanford in the Bio-X program, which I direct. These kinds of novel, interdisciplinary collaborations have been incredibly transformative. It’s one thing to sit around and talk about this really cool idea for a collaboration with a colleague in a different field, and another thing to actually be able to launch it.

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